Long-Term Therapy with Growth Hormone: Bringing Sagacity to SAGHE

Abstract

GH is an anterior pituitary protein secreted by somatotrophs under complex neural, hormonal, and metabolic control (1). So named because of its remarkable effects on growth when in excess (gigantism-acromegaly) or deficient (dwarfism), the hormone also has profound metabolic actions, antagonizing insulin action, promoting lipolysis in fat, and augmenting protein synthesis. These actions facilitate the integration of growth with metabolism but may have deleterious effects when in excess, including the unmasking of diabetes and diabetic complications such as retinopathy and atherosclerosis (2). Moreover, the term “growth” encompasses and envisions both normal and aberrant growth as occurs in neoplasia. Whereas deficiency of GH signaling pathways in diverse organisms such as yeast, mice, and man extends life span and decreases cancer (3), circumstantial and in vitro evidence suggests a role for IGF-I in inducing cancer in man (4). These considerations guide the ethical use of GH therapy for a variety of disorders in childhood characterized by short stature; concerns that GH may have deleterious effects that outweigh benefits surface periodically (5). GH has now been available for such treatment for over 50 yr. Initially extracted from cadaveric pituitaries, the materials were made available only to investigators for human studies via centralized, government-sponsored agencies, which also facilitated centralized monitoring of beneficial or adverse events. The use of such pituitaryextracted GH was discontinued in 1985 after the tragic occurrence of Jakob Creutzfeldt disease was recognized in several recipients in the United States and elsewhere. The tragedy of Jakob Creutzfeldt disease was particularly painful in France, where it received wide media attention, earned stiff penalties for those held responsible for GH distribution, and caused introspection for those charged with preventing such tragedies resulting from the use of GH in the future (6). Almost simultaneously, recombinant DNA-derived GH became available in abundance, enabling the broadening of indications to various forms of short stature and other entities such as chronic renal failure and AIDS wasting. Monitoring of potential adverse events was rigorously maintained by government agencies, pharmaceutical companies, the Pediatric Endocrine Society, and related organizations in the United States and throughout the world. With the exception of the use of GH for critically ill adults, which resulted in increased mortality (7) for the most part, despite valid concerns (5), the outcomes of children treated with GH have remained remarkably free of serious complications (8–12). For example, a recent analysis of safety and efficacy of GH treatment in 54,996 children monitored over a period of 20 yr (1985–2006), revealed an overall favorable safety profile without an increased risk of leukemia, a concern still expressed despite no evidence to support this concern from scientific reports over the past 25 yr (9). However, the study did identify an increased risk for a second neoplasm in those who previously received irradiation. Similarly, an increased risk for a second neoplasm in long-term survivors of childhood cancer treated with GH has been reported, although risk diminished with increased length of follow-up in this report from the Childhood Cancer Survivor Study (12). In children without a history of prior cancer or conditions that might predispose to cancer, no evidence for increased risk of cancer relative to that expected in the normal population was found in the KIGS (Pfizer International Growth Database) study as recently reported (8). None of these extensive databases have to date reported excess mortality from cardiovascular causes, and all emphasize the importance of continued and